Cell cycle is an important part of cell life activity. During normal cell growth, cell cycle progression depends on precise and tight regulation of cell cycle by regulatory factors at all levels. Among the regulatory factors, the core is cyclin dependent kinase (CDK) and its positive and negative regulatory factor—cyclin and cyclin dependent kinase inhibitor (CDI). CDK-cyclin complex formed by cyclin dependent kinase and cyclin is involved in cell growth, proliferation, dormancy or apoptosis. During cell cycle, cyclins are periodically and continuously expressed and degraded, and binds respectively to CDKs transiently activated by them. The promotion and transformation of different phases of the cell cycle are achieved by catalyzing the phosphorylation of different substrates through CDK activity.
Currently, there have been found 13 members of CDK family: CDK1-CDK13; among them, CDK1, CDK2, CDK3, CDK4 and CDK6 are involved in the regulation of cell proliferation, and CDK7, CDK8, CDK9, CDK11, CDK12 and CDK13 are involved in the regulation of transcription.
Cyclin is divided into cyclin A-L, different CDKs associate with different subtypes of cyclin. Among them, cyclin D family (cyclin D1, D2, D3) is expressed in the G1 phase, and binds and activates CDK4 and CDK6 to form a CDK4/6-cyclin D complex, which phosphorylates a series of substrates including retinoblastoma protein (Rb). Phosphorylated Rb releases proteins that bind to and are inhibited by it, mainly transcription factor E2F and others. E2F is activated and initiates transcription of some genes necessary for entry into the S phase (Ma. K., Advances in the Antitumor Effects of CDK4/6 inhibitor, World Notes on Antibiotics, 2013, 34(5): 197-202). If the balance is broken due to various factors, whether the signal for the promotion of cell proliferation is enhanced, or the signal for inhibition of cell proliferation is decreased to some extent, cell proliferation will be out of control, and then the tumor occurs. Studies have found that approximately 80% of human cancers have abnormalities in cyclin D-CDK4/6-INK4-Rb pathway (1. Malumbres M, Barbacid M., To cycle or not to cycle: a critical decision in cancer[J]. Nature Reviews Cancer, 2001, 1(3):222; 2. Shapiro G I., Cyclin-dependent kinase pathways as targets for cancer treatment[J]. J Clinical Oncology, 2006, 24(11):1770). Changes in this pathway accelerate the G1 phase progression, making tumor cell proliferation faster and gain survival advantage. Therefore, intervention on it has become a therapeutic strategy and CDK4/6 has therefore become one of the potential anti-tumor targets.
The advantage of CDK4/6 as an anti-tumor target is that: (1) most of the proliferating cells rely on CDK2 or CDK4/6 to proliferate, but CDK4/6 inhibitor does not exhibit similar cytotoxicity as a “pan-CDK inhibitor”, such as myelosuppression and intestinal reaction; (2) preclinical experiments show that increase of the cell level of cyclin D or inactivation of p16INK4a can increase the drug sensitivity of cells, due to the above phenomenon exists in tumor cells relative to normal cells, the drug targeting is increased to some extent.
In addition to inhibition of tumor growth, CDK inhibitors are also used in the treatment of other disorders, such as cardiovascular disorders, including atherosclerosis, vascular restenosis after stent implantation and other cardiovascular disorders caused by abnormal cellular proliferation; diseases caused by fungi, protozoan parasite (such as Plasmodium falciparum) and DNA and RNA virus infections, including malaria, AIDS and the like. In addition, studies have also found that CDK inhibitors can also be used for autoimmune diseases (such as psoriasis, rheumatoid arthritis, glomerulonephritis and lupus erythematosus, etc.), to inhibit the proliferation of inflammatory cells.
Since WO9811095 disclosed a series of 2-pyrimidine amine compounds having cell kinase inhibitory activity, many of the compounds believed to have CDK4/6 inhibitory activity have been developed based on such a parent structure in the prior art, some of which have become promising candidate drugs, and even entered the phase III clinical trials. For example, compound PD0332991, disclosed in WO2003062236, is also known as Palbociclib. It has a structure as shown in Formula 1, and is developed by Pfizer Pharmaceuticals Ltd. PD0332991 inhibited CDK4 and CDK6 with IC50 being 11 nmol/L and 15 nmol/L, respectively; whereas in the case of inhibiting CDK2, CDK1 and CDK5, IC50 being greater than 10 μmol/L (Fry D W, Harvey P J, Keller P R, et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts [J]. Molecular Cancer Therapeutics, 2004, 3(11): 1427). Compound LEE011 (disclosed in WO2011101409) developed by Novartis Pharmaceuticals has a structure as shown in Formula 2. Compound LY2835219 (disclosed in WO2010075074), also known as Bemaciclib, has a structure as shown in Formula 3; it has been reported to inhibit CDK4 and CDK6 with IC50 being 2 nmol/L and 9.9 nmol/L respectively (Lawrence M. G., S. F. Cai, X. Lin et al. Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine[J]. Invest New Drugs, (2014), 32: 825). Currently, Phase III clinical trials are being conducted by Eli Lilly and Company on LY2835219.

Due to the appearance of these compounds, CDK4/6 has become an explicit anti-tumor target. It is necessary and urgent to develop a CDK4/6 inhibitor with a better selectivity, activity and bioavailability, which may provide more clinical options for the treatment of diseases associated with abnormal cell proliferation, such as cancer.